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当代阿耳茨海默病研究

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Research Article

Poloxamer-188 加剧 5XFAD 小鼠的脑淀粉样变性、突触前营养不良和致病性小胶质细胞活化

卷 19, 期 4, 2022

发表于: 15 June, 2022

页: [317 - 329] 页: 13

弟呕挨: 10.2174/1567205019666220509143823

价格: $65

摘要

背景：阿尔茨海默病 (AD) 是由脑实质中淀粉样 β (Aβ) 蛋白的异常积累引发的。淀粉样斑块周围的微环境的特点是与溶酶体功能障碍、微管破坏和轴突运输受损相关的突触前末端（营养不良性神经突）肿胀。 Aβ诱导的质膜损伤和钙内流可能是营养不良神经突形成的潜在机制。 目的：我们测试了通过大脑给予安全的 FDA 批准的表面活性剂分子泊洛沙姆-188 (P188) 来促进膜完整性是否可以减轻体内 AD 病理学。 方法：用微型渗透泵在 3 个月大的 5XFAD 雄性小鼠的大脑中给予多种浓度的 P188 42 天。 42 天后，对小鼠实施安乐死并评估大脑中的淀粉样蛋白病理学、营养不良性神经突、致病性小胶质细胞激活、tau 磷酸化和溶酶体/水泡运输标志物。 结果：P188在最高浓度10mM时致死。较低浓度的 P188（1.2、12 和 120μM）具有良好的耐受性。 P188 可能通过激活 γ-分泌酶途径增加脑 Aβ 负荷。如 Aβ 沉积物周围的 LAMP1 积累增加所示，在 P188 处理的小鼠中，营养不良的神经突病理恶化。 P188 增加了致病性小胶质细胞的活化。总 tau 水平降低了 P188。溶酶体酶组织蛋白酶 D 和钙依赖性水泡运输调节剂 synaptotagmin-7 (SYT7) 在 P188 给药后失调。 结论：P188 脑递送加剧了 5XFAD 小鼠的淀粉样蛋白病理、营养不良性神经突和致病性小胶质细胞活化。这些影响与溶酶体功能障碍和质膜囊泡运输的失调有关。 P188 不是针对 AD 发病机制的有前途的治疗策略。

关键词: 阿尔茨海默病、泊洛沙姆-188、营养不良性神经突、淀粉样蛋白、γ-分泌酶、小胶质细胞、突触结合蛋白-7。

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